Ig-like transcript 4 (ILT4) (also known as leukocyte Ig-like receptor 2, CD85d, and LILRB2) is a cell surface receptor expressed mainly on myelomonocytic cells, whereas ILT2 (also known as leukocyte Ig-like receptor 1, CD85j, and LILRB1) is expressed on a wider range of immune cells including subsets of natural killer and T cells. Both ILTs contain immunoreceptor tyrosine-based inhibitory receptor motifs in their cytoplasmic tails that inhibit cellular responses by recruiting phosphatases such as SHP-1 (Src homology 2 domain containing tyrosine phosphatase 1). Although these ILTs have been shown to recognize a broad range of classical and nonclassical human MHC class I molecules (MHCIs), their precise binding properties remain controversial. We have used surface plasmon resonance to analyze the interaction of soluble forms of ILT4 and ILT2 with several MHCIs. Although the range of affinities measured was quite broad (K d ‫؍‬ 2-45 M), some interesting differences were observed. ILT2 generally bound with a 2-to 3-fold higher affinity than ILT4 to the same MHCI. Furthermore, ILT2 and ILT4 bound to HLA-G with a 3-to 4-fold higher affinity than to classical MHCIs, suggesting that ILT͞HLA-G recognition may play a dominant role in the regulation of natural killer, T, and myelomonocytic cell activation. Finally, we show that ILT2 and ILT4 effectively compete with CD8 for MHCI binding, raising the possibility that ILT2 modulates CD8 ؉ T cell activation by blocking the CD8 binding as well as by recruiting inhibitory molecules through its immunoreceptor tyrosine-based inhibitory receptor motif.leukocyte Ig-like receptors ͉ major histocompatibility complex ͉ surface plasmon resonance ͉ natural killer cell ͉ coreceptor I g-like transcripts (ILTs) (also called leukocyte Ig-like receptors, CD85, or LILRB) are encoded by a family of immunoreceptor genes located at human chromosome 19q13.4. This locus is called the leukocyte receptor complex and includes, in addition to ILT genes, the genes encoding killer cell Ig-like receptors (KIRs), leukocyte-associated Ig-like receptors, NKp46, and the Fc␣ receptor (1). Although ILT2 is broadly expressed on monocytes, B cells, dendritic cells, and subsets of natural killer (NK) and T cells, ILT4 expression is largely confined to the myelomonocytic lineage (2-8). Both ILT2 and ILT4 have four tandem Ig-like extracellular domains and four and three immunoreceptor tyrosine-based inhibitory receptor motifs, respectively, in their cytoplasmic tails. Immunoreceptor tyrosine-based inhibitory receptor motifs recruit the protein tyrosine phosphatase SHP-1 (Src homology 2 domain containing phosphatase 1), which is thought to inhibit early signaling events triggered by stimulatory receptors. Indeed engagement of ILT2 on T cells has been shown to inhibit T cell antigen receptor (TCR) signaling and downstream events such as actin reorganization (9). Studies on CD8 ϩ cells suggest that ILT2 is expressed early on in contrast to KIRs, which are expressed primarily on the subset of stimulated CD8 ϩ cells tha...

BACKGROUND. Cryptococcal meningitis (CM) remains a leading cause of acquired immunodeficiency syndrome-related death in sub-Saharan Africa. The timing of the initiation of antiretroviral therapy (ART) for human immunodeficiency virus (HIV)-associated CM remains uncertain. The study aimed to determine the optimal timing for initiation of ART in HIV-positive individuals with CM. METHODS. A prospective, open-label, randomized clinical trial was conducted at a tertiary teaching hospital in Zimbabwe. Participants were aged > or = 18 years, were ART naive, had received a first CM diagnosis, and were randomized to receive early ART (within 72 h after CM diagnosis) or delayed ART (after 10 weeks of treatment with fluconazole alone). Participants received 800 mg of fluconazole per day. The ART regimen used was stavudine, lamivudine, and nevirapine given twice daily. The duration of follow-up was up to 3 years. The primary end point was all-cause mortality. RESULTS. Fifty-four participants were enrolled in the study (28 in the early ART arm and 26 in the delayed ART arm). The median CD4 cell count at enrollment was 37 cells/mm(3) (interquartile range, 17-69 cells/mm(3)). The 3-year mortality rate differed significantly between the early and delayed ART groups (88% vs 54%; P < .006); the overall 3-year mortality rate was 73%. The median durations of survival were 28 days and 637 days in the early and delayed ART groups, respectively (P = .031, by log-rank test). The risk of mortality was almost 3 times as great in the early ART group versus the delayed ART group (adjusted hazard ratio, 2.85; 95% confidence interval, 1.1-7.23). The study was terminated early by the data safety monitoring committee. CONCLUSIONS. In resource-limited settings where CM management may be suboptimal, when compared with a delay of 10 weeks after a CM diagnosis, early initiation of ART results in increased mortality. Trial registration. ClinicalTrials.gov identifier: NCT00830856.

Child stunting and anemia are intractable public health problems in developing countries and have profound short- and long-term consequences. The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial is motivated by the premise that environmental enteric dysfunction (EED) is a major underlying cause of both stunting and anemia, that chronic inflammation is the central characteristic of EED mediating these adverse effects, and that EED is primarily caused by high fecal ingestion due to living in conditions of poor water, sanitation, and hygiene (WASH). SHINE is a proof-of-concept, 2 × 2 factorial, cluster-randomized, community-based trial in 2 rural districts of Zimbabwe that will test the independent and combined effects of protecting babies from fecal ingestion (factor 1, operationalized through a WASH intervention) and optimizing nutritional adequacy of infant diet (factor 2, operationalized through an infant and young child feeding [IYCF] intervention) on length and hemoglobin at 18 months of age. Within SHINE we will measure 2 causal pathways. The program impact pathway comprises the series of processes and behaviors linking implementation of the interventions with the 2 child health primary outcomes; it will be modeled using measures of fidelity of intervention delivery and household uptake of promoted behaviors and practices. We will also measure a range of household and individual characteristics, social interactions, and maternal capabilities for childcare, which we hypothesize will explain heterogeneity along these pathways. The biomedical pathway comprises the infant biologic responses to the WASH and IYCF interventions that ultimately result in attained stature and hemoglobin concentration at 18 months of age; it will be elucidated by measuring biomarkers of intestinal structure and function (inflammation, regeneration, absorption, and permeability); microbial translocation; systemic inflammation; and hormonal determinants of growth and anemia among a subgroup of infants enrolled in an EED substudy. This article describes the rationale, design, and methods underlying the SHINE trial.Clinical Trials Registration. NCT01824940.